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This is an important paper. It appears as one of very few examples of delineated risk factors for AD for which a plausible function linked to Aβ degradation is clearly documented. Of most interest, obviously, is the observation that an AD-linked mutation could directly impair the Aβ-SORLA interaction and lead to enhanced Aβ levels, thereby bringing a biological rational for the original genetic observation. This adds a bit more support to the amyloid cascade hypothesis. In sporadic AD, there are no clues of enhanced Aβ formation. Rather, it is the decrease of degradation rates that leads to increased cerebral loads of peptides.

This paper further supports the view that Aβ levels are modulated downstream of secretase actions. Both SORLA levels that are diminished in sporadic AD-affected brains and mechanisms of action of SORLA support the view that this receptor contributes to sporadic AD. The fact that the mutation the authors examined, located in the SORLA domain that interacts with Aβ, affects SORLA function is interesting. The question to address is whether other SORLA mutations located outside this VPS10P domain trigger the same effect. It is possible that mutations outside the binding domain could alter the 3-D structure to ultimately affect lysosomal Aβ degradation. Alternatively, it remains possible that additional AD-linked mutations enhance AD risk by affecting other pathways, even unrelated to APP trafficking/processing.